pharmacogenomics

Question 1

what is the mechanism of action of mercaptopurine ?

Answer 1

mercaptopurine is a purine antimetabolite or purine antagonist and as such inhibits DNA synthesis by inhibiting production of the purine containing nucleotides, adenine and guanine, thus halting DNA synthesis.

mercaptopurien competes with the purine derivatives hypoxanthine and guanine for the enzyme HGPRT and itself converted to TIMP

TIMP and its methylated derivative, MTIMP, also inhibit other enzymes in nucleobase synthesis

Preferential killing of the most proliferative (cancer) cells in the bone marrow.

Question 2

what can too much of 6-MP cause in the body ?

Answer 2

Diarrhoea, nausea, vomiting, loss of appetite, fatigue

Mouth sores, fever, sore throat, easy bruising or bleeding, pinpoint red spots on the skin, yellowing of eyes or skin, dark/bloody stools, dark/bloody urine, and painful or difficult urination.

Further bone marrow suppression=myelosuppression: severe immune issues
Death

Question 3

why can can cause reduced activity of TPMT

Answer 3

The enzyme TPMT Thiopurine S-methyltransferase has reduced activity because of mutation in some individuals
TPMT activity exhibits genetic variation and shows ti-modal population distribution

Question 4

how is IBD dose treatment adjusted based on TPMT enzyme activity ?

Answer 4

pre treatment:
Screen for viral infections: Hepatitis B (surface antigen and core antibody), Hepatitis C, HIV, and Epstein-Barr virus (EBV).

Check TPMT enzyme activity to assess patient’s ability to metabolize thiopurines.

if zero pmt activity avoid thiopurien and use alternative
if heterozygous or carrier use lower doses

if normal or high tempt activity then use standard doses

FBC/LFT monitoring

Question 5

what allele shows key variants with TPMT activity?

Answer 5

TPMT*1C